Patients with metastatic medullary thyroid cancer (MTC) have a poor prognosis. Recently, vandetanib, a multikinase inhibitor, was approved for treating patients with progressive metastatic MTC creating a new first-line therapy. However, in several studies using vandetanib and other multikinase inhibitors in MTC, complete responses did not occur and acquired resistance was common. Thus, there is a crucial need to develop effective second line treatments. While all of the compounds that have an effect on progression free survival in MTC inhibit a variety of kinases, all include Ret and VEGFR2 in their targets suggesting similar mechanisms of action. However, of the studied kinase inhibitors, only sorafenib also inhibits Raf kinases suggesting potentially unique synergies. In preliminary data it is shown that, as predicted by cell signaling data the combination of sorafenib with a Mek inhibitor is synergistic. These data, along with previously published in vivo data from other groups in other cancers establishing tolerability, suggest this combination might be a reasonable alternative to explore in vandetanib-resistant MTC. It is also recognized that other pathways may be responsible for vandetanib resistance that remain to be identified. Ret is a common target of the compounds studied in MTC. While activating RET mutations in the germline cause of inherited MTC, somatic mutations are found in only ~40% of sporadic tumors, suggesting other pathways may also cause MTC. Activation of cyclin dependent kinases (CDK) through knock down of CDK inhibitors or inactivation of retinoblastoma (Rb) cause MTC in mice. In addition, it is shown in preliminary data that CDK pathway activation and gene abnormalities are common in human MTC. Taken together, these results suggest CDKs are a rational therapeutic target for MTC. Thus, in Project 3 we propose to test the following hypotheses: 1) Combination therapy using sorafenib/MEK inhibitor is effective in patients with metastatic vandetanib- resistant MTC and novel pathways of vandetanib resistance can be identified that predict synergy and 2) CDK inhibitors are active as phmary;Single therapy or in combination as a therapy for metastatic progressive MTC and CDK pathway activation predicts metastases. RELEVANCE (See instructions): Metastatic progressive MTC is currently an incurable disease. Despite recent advances in therapy with multikinase inhibitors, even patients that initially respond acquire resistance and progress over time. Project 3 focuses on this critical need to develop new second-line strategies for patients with MTC and to identify novel targets for combinatorial and single treatment strategies making it highly relevant for cancer therapy.